The development of pharmacological treatment regimens for heroin addicts has been in the forefront of therapeutic approaches to narcotics addiction. Both narcotic analgesics such as methadone and narcotic antagonists such as naloxone have been used clinically. The longterm goal of the proposed research is to elucidate the mechanisms of action of opioids and antagonists at the cellular level using electrophysiological and neuropharmacological techniques. The specific aims for this project period, developed primarily on the basis of pilot studies on naloxone- induced reflex enhancement, involve the study of the effects of naloxone and morphine in acute and chronic spinal cats and rats. Drug effects will be studied on both spinal reflexes recorded on ventral roots, and on single motoneurons using intra-cellular recording and stimulation. Interactions between morphine and naloxone will be studied to determine whether morphine (in single doses or after chronic administration) increases the sensitivity of spinal pathways to the effects of naloxone. The development of tolerance to morphine will be studied with respect to the relationship between pharmacologically effective doses and the chronic doses required to produce tolerance. The investigation of effects of naloxone is important because naloxone is often considered to be a pure narcotic antagonist with no actions of its own. It is for this reason that a long acting formulation seems especially attractive for therapeutic use. These studies also have significant implications for the interpretation of experimental studies of addiction in which narcotic antagonists are used to precipitate withdrawal.